Valentina Shakhnovich1, P Brian Smith2, Jeffrey T Guptill3, Laura P James4, David N Collier5, Huali Wu2, Chad E Livingston6, Jian Zhao7, Gregory L Kearns4. 1. Divisions of Gastroenterology & Clinical Pharmacology, Toxicology and Therapeutic Innovation, The Children's Mercy Hospital, Kansas City, MO. Electronic address: vshakhnovich@cmh.edu. 2. Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Duke Clinical Research Institute, Durham, NC. 3. Department of Neurology, Division of Neuromuscular Medicine, Duke Clinical Research Institute, Durham, NC. 4. Department of Pediatrics, University of Arkansas for Medical Sciences Section of Clinical Pharmacology and Toxicology, Arkansas Children's Hospital, Little Rock, AR. 5. Department of Pediatrics and Center for Health Disparities, Division of General Pediatrics, East Carolina University, Greenville, NC. 6. Clinical Operations, Pediatric Trials Network. 7. The Emmes Statistical Group, Rockville, MD.
Abstract
OBJECTIVE: To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. STUDY DESIGN: A total of 41 obese children (6-17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ~1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula. Ten post-dose pantoprazole plasma concentrations were measured, and PK variables generated via noncompartmental methods (WinNonlin). Linear and nonlinear regression analyses and analyses of variance were used to explore obesity, age, and CYP2C19 genotype contribution to pantoprazole PK. PK variables of interest were compared with historic nonobese peers treated with pantoprazole. RESULTS: Independent of genotype, when normalized to dose per kg total body weight, pantoprazole apparent clearance and apparent volume of distribution were significantly lower (P < .05) and systemic exposure significantly higher (P < .01) in obese vs nonobese children. When normalized per kg LBW, these differences were not evident in children ≥12 years of age and markedly reduced in children <12 years of age. CONCLUSIONS: LBW dosing of pantoprazole led to pantoprazole PK similar to nonobese peers. Additional factors, other than body size (eg, age-related changes in CYP2C19 activity), appear to affect pantoprazole PK in children <12 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02186652.
OBJECTIVE: To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. STUDY DESIGN: A total of 41 obese children (6-17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ~1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula. Ten post-dose pantoprazole plasma concentrations were measured, and PK variables generated via noncompartmental methods (WinNonlin). Linear and nonlinear regression analyses and analyses of variance were used to explore obesity, age, and CYP2C19 genotype contribution to pantoprazole PK. PK variables of interest were compared with historic nonobese peers treated with pantoprazole. RESULTS: Independent of genotype, when normalized to dose per kg total body weight, pantoprazole apparent clearance and apparent volume of distribution were significantly lower (P < .05) and systemic exposure significantly higher (P < .01) in obese vs nonobese children. When normalized per kg LBW, these differences were not evident in children ≥12 years of age and markedly reduced in children <12 years of age. CONCLUSIONS: LBW dosing of pantoprazole led to pantoprazole PK similar to nonobese peers. Additional factors, other than body size (eg, age-related changes in CYP2C19 activity), appear to affect pantoprazole PK in children <12 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02186652.
Authors: Catherijne A J Knibbe; Margreke J E Brill; Anne van Rongen; Jeroen Diepstraten; Piet Hein van der Graaf; Meindert Danhof Journal: Annu Rev Pharmacol Toxicol Date: 2014-10-17 Impact factor: 13.820
Authors: Gregory L Kearns; Jeffrey Blumer; Stephen Schexnayder; Laura P James; Kim G Adcock; Michael D Reed; James F Daniel; Andrea Gaedigk; Jeffrey Paul Journal: J Clin Pharmacol Date: 2008-07-29 Impact factor: 3.126
Authors: Christiana J Bernal; Ida Aka; Robert J Carroll; Joseph R Coco; John J Lima; Sari A Acra; Dan M Roden; Sara L Van Driest Journal: Pediatrics Date: 2019-11-07 Impact factor: 7.124
Authors: Kathryn E Kyler; Jonathan Wagner; Chelsea Hosey-Cojocari; Kevin Watt; Valentina Shakhnovich Journal: Paediatr Drugs Date: 2019-10 Impact factor: 3.022
Authors: V Shakhnovich; S Abdel-Rahman; C A Friesen; J Weigel; R E Pearce; A Gaedigk; J S Leeder; G L Kearns Journal: Pediatr Obes Date: 2018-09-26 Impact factor: 4.000
Authors: Valentina Shakhnovich; P Brian Smith; Jeffrey T Guptill; Laura P James; David N Collier; Huali Wu; Chad E Livingston; Jian Zhao; Gregory L Kearns; Michael Cohen-Wolkowiez Journal: Paediatr Drugs Date: 2018-10 Impact factor: 3.930
Authors: Valentina Shakhnovich; Christoph P Hornik; Gregory L Kearns; Jaylene Weigel; Susan M Abdel-Rahman Journal: Clin Transl Sci Date: 2019-03-18 Impact factor: 4.689
Authors: Thomas P Green; Helen J Binns; Huali Wu; Adolfo J Ariza; Eliana M Perrin; Maheen Quadri; Christoph P Hornik; Michael Cohen-Wolkowiez Journal: Clin Transl Sci Date: 2020-11-22 Impact factor: 4.438